In connection with performing medical diagnostics on the brain, it is often helpful to measure the variation, contraction or dilation, of blood vessels in the brain.
Currently known methods involve injection of radioactive or contrast-enhancing substances into the bloodstream in order to observe and learn about variations in blood flow in the brain between migraine attacks and normal conditions. Examination is also possible by the invasive method of introducing probes (electrodes) directly into the brain.
Currently known measurement methods for measuring blood flow to and in the brain include Isotope Diagnosis (ID) and Transcranial Doppler ultrasonography (TCD). Isotope Diagnosis is invasive and can only be performed by intermittent sampling measurements, rather that continuous measurement in real-time.
TCD is noninvasive and does give real-time measurement. However, the accuracy of the measurement is highly dependent upon the angle of the probe relative to the skull, and the skill of the operator. In addition, TCD does not measure the volumetric velocity of the blood flow and does not give precise measurement of the contraction or dilation of blood vessels in the brain. This imprecision is caused by the fact that TCD can only be used to observe a sector or large area in the brain, instead of a localized point. In addition, TCD uses ultrasound waves at a frequency of 2 MHz, which, for an estimated 15-40% of the population, do not actually reach the interior of the cranium, because of high attenuation of the ultrasound waves in the bone tissue of the cranium. In those cases, where there is a response from the skull or via "acoustic windows," such as the temporal bones (orbital regions or foramen occipital magna), the acoustic reflections detected are only from the magistrial and proximal blood vessels. In addition to these reflected signals, this method also detects reflections from the brain and from other, non-cranial, blood vessels. The result is a noisy signal that does not allow precise determination of the depth of the measurement point. This does not allow measurement of individual blood vessels or their blood flow with any precision. Use of ultrasound technology as a diagnostic tool is discussed, inter alia, in the book entitled "Textbook of Diagnostic Ultrasonography," 4.sup.th edition, by Mosby, pages 682-686.
It is also useful in connection with medical diagnostics of the brain to initially determine, and then monitor over time, the pressure in the brain. This pressure is commonly referred to in the art as intra-cranial pressure.
As a general rule, tissues in the body swell when traumatized. In order to heal, such tissues require oxygen. There are special circumstances with respect to brain tissue which makes the situation even more critical. The brain rests inside a bone casing, and there is little or no room for it to expand. When the brain swells, it experiences more trauma. Because it is encased within the skull, the swelling of the brain causes parts of the brain to be compressed. This compression decreases the blood flow and oxygen to parts of the brain which, in turn, causes more swelling. The more damage the brain receives, the more oxygen it needs, and the more it swells. Swelling is caused, e.g., by leakage from blood vessels. This leads to a rise in pressure within the brain. This rise in pressure rapidly equals the arterial pressure, thereby effecting the blood flow to the brain. The diffused pressure which decreases blood flow affects the ability of the cells within the brain to metabolize properly. The cells are unable to eliminate toxins, which toxins then accumulate in the brain. This phenomenon leads to a spiraling effect, which in effect is what kills brain-injured individuals who do not get prompt medical attention.
In response to a trauma, changes occur in the brain which require monitoring to prevent further damage. The size of the brain frequently increases after a severe head injury. This is referred to in the art as "brain swelling" and occurs when there is an increase in the amount of blood in the brain. Thereafter, water may collect in the brain (referred to in the art as "brain edema"). Both brain swelling and brain edema result in excessive pressure in the brain. The pressure in the brain is referred to in the art as intracranial pressure ("ICP"). It is essential that excessive ICP be identified and monitored so that it can be immediately treated. Treatment of brain swelling can be difficult, but it is very important because brain swelling in turn causes reduced amounts of both oxygen and glucose available to the brain tissue. Oxygen and glucose are both required by the brain to survive. The cranial cavity of the skull contains approximately 78% brain, 12% blood and vessels, and 10% cerebrospinal fluid (CSF). Intracranial volumes enclosed within the rigid container of the skull are fixed. An increase in the volume of one of these components requires an equivalent decrease in another of these components in order for the volume in pressure to remain constant. Increases in ICP occur as a result of this volume-pressure relationship. When there is an increase in any of these three components, the body tries to compensate by reabsorbing CSF and decrease intracellular volume.
In order to treat excessive ICP, physicians have a number of different methods available at their disposal, including the use of medications which help draw fluid out of the brain and into blood vessels; medications which decrease the metabolic requirements of the brain; medications which increase blood flow into the brain; and surgical procedures which are used to either reduce small amounts of fluid or remove the damaged brain tissue.
Surgical procedures further include removing any hematomas (blood clots) which are pressing on the brain, or surgically repairing damaged blood vessels to stop any further bleeding. In severe cases, portions of the brain that have been damaged beyond recovery may be removed in order to increase chances of recovery for the healthy portions of the brain. A shunt or ventricular drain may be used to drain off excess fluids. The overall goal of the neurosurgeon is to maintain blood flow and oxygen to all parts of the brain, thereby minimizing the damage and increasing the prospect of survival and recovery.
The normal values for intracranial pressure (ICP) at the level of foramen of Monro are approximately 90-210 mm of CSF in adults and 15-80 mm of CSF in infants. Increased ICP can occur as a result of an increased mass within the limited volume of the cranium. Examples include an increase in CSF volume, cerebral edema, and growing mass lesions such as tumors and hematomas. Cerebral edema is the increase in brain tissue water causing swelling. It may occur secondary to head injury, infarction or a response to adjacent hematoma or tumor. Uncorrected increased ICP can lead to further brain damage due to the pressure and inadequate blood perfusion of neurological tissues. The treatment for increased ICP includes removing the mass (tumor, hematoma) by surgery, draining CSF from the ventricles by a drain or a shunt, hyperventilation, steroids, osmotic dehydrating agents, and barbiturates.
Increased ICP will reduce cerebral blood flow, leading to ischemia. If blood flow is constricted for more than four minutes, an individual can experience irreversible brain damage. With constricted blood flow, cells become damaged, leading to more edema, causing more increased ICP.
The principle causes of elevated ICP include traumatic head injury (e.g., edema, intracranial hemorrhage, and hydrocephalus), infection, and tumors.
Treatment of elevated ICP can be accomplished by CSF drainage; decreasing the edema via the use of strong drugs such as diuretics; ventilation (mechanical and hyperventilation); cerebral perfusion pressure control (blood pressure control, fluid restriction); and promoting venous blood return; and intracranial surgery.
Most clinicians consider 20 mm Hg as the upper limited of acceptable ICP, beyond which treatment is initiated. The key to treatment is to control cerebral perfusion pressure (CPP) or the adequate flow of blood and oxygen to the brain cells. It has been shown that by monitoring ICP, treating brain edema and giving appropriate treatment, death and disability in humans can be decreased by more than 50%. Despite this positive outcome, monitoring of ICP was shown to be done in only 30% of patients with severe head injury, according to a survey of U.S. Trauma Centers.
The United States market for head injury is substantial with several unmet needs. In the United States, there are approximately two million cases of head injury per year. There are approximately 60,000 deaths per year due to head injury, with 500,000 hospital admissions per year and 20,000 in-hospital deaths per year due to head injury. Approximately 80,000 head injury survivors per year have a significant loss of function and require long-term medical and rehabilitation care. In fact, head injury is the leading cause of death and disability in ages 1-44. There are over 100,000 neurosurgical procedures done per year in the United States.
In the case of a head trauma, ICP can change significantly in a matter of minutes. Significant changes in ICP may also occur hours, days, or weeks, from diagnosis of the underlying trauma or disease state. It is therefore advantageous to continually monitor the ICP of a patient in an emergency room setting, in a surgical setting, and at a patient's bedside.
Currently, the vast majority of ICP measurements are performed invasively, using needles, catheters, and implants.
In lumbar puncture, a needle is inserted at the base of the spinal column, to monitor the pressure of the fluid in the spinal column. This pressure may not reflect accurately the ICP, because there may be a blockage between the patient's head and the base of the patient's spinal column.
A second invasive method of monitoring ICP is to make a burr hole 5-10 mm in diameter in the patient's skull and to introduce a catheter to one of the lateral ventricles via the hole. The pressure of the cerebrospinal fluid (CSF) in the ventricle is measured directly by a transducer via the catheter. This procedure may cause a hemorrhage that blocks the penetrated ventricle. In addition, if CSF enters the catheter, the accuracy of the pressure reading is impaired.
In a related invasive method, the catheter is held in place by a threaded fitting that is screwed into the patient's skull. A saline solution is introduced to the catheter and the pressure of the saline solution is measured using an appropriate transducer. If insufficient care is taken to preserve antiseptic conditions, this procedure may lead to infection of the patient's brain. Furthermore, the threaded fitting may penetrate the patient's brain, causing damage to the patient's brain.
In both of the latter two invasive methods, the catheter must be removed after five days. Therefore, these methods cannot be used for long term (several months) monitoring of ICP of patients in comas.
In a fourth invasive method, a fiber optic device, with a sensor at the tip of a fiber optic cable (available from Codman, a Johnson & Johnson Company), is inserted in the patient's cerebral tissue, in the patient's subdural space, or in the patient's intraventricular and epidural space. If a blood clot forms on the sensor, or if the fiber optic cable bends too sharply or breaks, the device may give a spuriously high pressure reading.
In short, the prior art invasive methods of measuring ICP are unreliable, may lead to infection, and cannot be used for more than five consecutive days.
There are also additional drawbacks to invasive techniques. Due to the problems associated with invasive techniques for measuring ICP, standard medical protocol is to monitor ICP only for patients with scores of 8 or less on the Glascow Coma Scale. It would be useful to monitor ICP of patients with Glascow scores higher than 8. It would also be useful to monitor ICP in healthy individuals under severe environmental stress, such as astronauts, divers, and submariners.
A number of non-invasive techniques for measuring ICP have been proposed in the literature. However, for a variety of reasons, none of these methods have found significant commercial use.
For example, TCD has been used to provide a non-invasive, qualitative indication of variations in intra-cranial pressure ("ICP"). The use of TCD in the measurement of ICP is described, for example, in Schoser B. G. et al., "Journal of Neurosurgery" 1999, November: 91(5): 744-9; Nevell D. W., "New Horizons" 1995 August:3(3) 423-30, and PCT Publication WO 99/63890 to Taylor. Unfortunately, TCD only provides a qualitative indication of variations in ICP, and does not provide a quantitative measurement of ICP.
Attempts have been made to use TCD to obtain a quantitative measure of ICP using pulsatile (P.I.) and resistant (R.I.) indexes. However, according to the investigations done by Czosnika M. et al. "Journal of Neurosurgery", 1999, July 91 (1) 11-9; and Hanlo P. W. et al. Child Neuro. Syst. 1995; Oct; 11(10); 595-603 there is no linear relations between ICP and TCD indexes. Moreover, the accuracy of these TCD measurements is low, particularly in patients with raised ICP.
Additional non-invasive methods for measuring ICP include "classical acoustic methods" based on the transfer of acoustic waves via the skull, as discussed in U.S. Pat. Nos. 5,117,835 to Edvin et al, and in O. Pranevicius et al, Acta Neurol. Sound 1992:86:512-516; and the Pulse Phased Locked Loop (PPLL) method as discussed in U.S. Pat. No. 4,984,567 to Kagaiama and in Uenot et al. "Acta Neurochir. Suppl." Wien 1998:71:66-9. These methods infer ICP by monitoring dura mater, a thick and dense inelastic fibrous membrane which lines the interior of the skull and extends inward to support and protect the brain.
However, classical acoustic and PLL methods are dependent upon the patients' skull condition (e.g. skull fractures, skull thickness, and pneumocephalus) as well as the patient's body temperature and environmental temperature. Each of these variables may lead to largely inaccurate ICP measurements. An additional disadvantage of these methods derives from their use of the thickness of dura mater as an indication of ICP despite the fact that dura mater, in some patients, may be adhered to the internal table of the skull. Moreover, the ICP waves generated by these methods do not resemble the ICP waves generated by invasive methods. This raises additional problems because doctors and nurses are not accustomed to reading and interpreting these types of ICP waveforms.
U.S. Pat. No. 5,617,873 to Yost et al, purports to describe an indirect, noninvasive method of monitoring ICP. Two changes in CSF volume are induced, and the associated changes in ICP are measured.
Therefore, presently known methods of quantitatively determining ICP remain predominantly invasive despite the existence of various non-invasive methods in the scientific and patent literature, and the need for a non-invasive alternative.
In addition to ICP, it is also useful in medical diagnostics to diagnose and monitor midline shift. The presence of midline shift provides an indication that some space filling lesion has caused distortion of the brain contents and, upon identification of the particular responsible mass, is normally cause for prompt intervention. Acute insults would be expected to initially induce elevation of ICP, with midline shift occurring later. Midline shift and ICP are thought to be closely related indicators of functional brain status following head trauma. However, it is generally believed that midline shift is a somewhat less sensitive indicator of acute unilateral space filling lesions than ICP. On the other hand, midline shift could well be a more sensitive predictor of slowly developing lesions such as brain tumors, where it serves as a confirmatory diagnostic tool, secondary to CT and MRI scans.
Under normal conditions, the brain sits in the middle of the cranial cavity equally distant from the outer limits of either hemisphere of the cavity. The brain is protected on all sides by cerebrospinal fluid.
A patient can experience edema, hemorrhaging/hematoma or some other lesion in the brain that will result in a shift away from midline, away from the hemisphere where the mass has formed. The key events that can cause such a shift are: traumatic head injury; post surgical hemorrhaging; infection; cerebrospinal fluid buildup; and/or the presence of a tumor. The shift may occur very quickly following the event or after a period of time.
Midline shift is currently measured by CT Scan. Determining midline shift is considered an important diagnostic tool by both neurosurgeons and emergency medicine physicians. A patient in the emergency room of a hospital presenting with a head injury and a low Glasgow Coma Scale score (8 or less), would be sent for a CT Scan. If the CT Scan is abnormal, showing a mass with or without midline shift, the neurosurgeon would be consulted. Sometimes the initial CT Scan is normal and the patient needs to be monitored. The question always arises as to what point does the patient get a second or third CT Scan. CT Scans are expensive, and the patient is subjected to radio-opaque dyes and contrast agents. Sending a seriously injured patient from the ER for a CT Scan can take the patient away from maximum emergency medicine care. The report on midline shift is typically fed back to the emergency medicine physician by the radiologist and presented qualitatively by categorizing the shift as minimal or substantial. In contrast, a neurosurgeon can read the CT Scan directly and determine the amount of shift (typically in millimeters).
Therefore, it would be advantageous to provide a portable, inexpensive technique to quantify midline shift which would be readily used in an emergency room or at a patient's bedside.